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Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-01 , DOI: 10.1021/acs.jmedchem.0c00045 Fumiyuki Shirai , Anna Mizutani 1 , Yoko Yashiroda , Takeshi Tsumura , Yuko Kano , Yukiko Muramatsu 1 , Tsubasa Chikada , Hitomi Yuki , Hideaki Niwa , Shin Sato , Kenichi Washizuka , Yasuko Koda , Yui Mazaki , Myung-Kyu Jang 1, 2 , Haruka Yoshida 1 , Akiko Nagamori 1 , Masayuki Okue , Takashi Watanabe , Kouichi Kitamura , Eiki Shitara , Teruki Honma , Takashi Umehara , Mikako Shirouzu , Takehiro Fukami , Hiroyuki Seimiya 1, 2 , Minoru Yoshida 3 , Hiroo Koyama
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-01 , DOI: 10.1021/acs.jmedchem.0c00045 Fumiyuki Shirai , Anna Mizutani 1 , Yoko Yashiroda , Takeshi Tsumura , Yuko Kano , Yukiko Muramatsu 1 , Tsubasa Chikada , Hitomi Yuki , Hideaki Niwa , Shin Sato , Kenichi Washizuka , Yasuko Koda , Yui Mazaki , Myung-Kyu Jang 1, 2 , Haruka Yoshida 1 , Akiko Nagamori 1 , Masayuki Okue , Takashi Watanabe , Kouichi Kitamura , Eiki Shitara , Teruki Honma , Takashi Umehara , Mikako Shirouzu , Takehiro Fukami , Hiroyuki Seimiya 1, 2 , Minoru Yoshida 3 , Hiroo Koyama
Affiliation
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Tankyrases (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/β-catenin signaling, which plays an important role in cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent tankyrase inhibitor. Herein we describe the optimization process of RK-287107 leading to RK-582, which exhibits a markedly improved robust tumor growth inhibition in a COLO-320DM mouse xenograft model when orally administered. In addition to the dose-dependent elevation and attenuation of the levels of biomarkers AXIN2 and β-catenin, respectively, results of the TCF reporter and cell proliferation studies on COLO-320DM are discussed.
中文翻译：
口服有效的基于螺吲哚啉酮的坦科聚合酶抑制剂的设计与发现。
坦科聚合酶（TNKS / TNKS2）属于聚（ADP-核糖）聚合酶家族。抑制其酶活性会减弱Wnt /β-catenin信号传导，这在癌症发病机理中起着重要作用。我们以前曾报道过发现基于螺二氢吲哚的，高度选择性的，有效的坦科聚合酶抑制剂RK-287107。在这里，我们描述了导致RK-582的RK-287107的优化过程，该过程在口服时在COLO-320DM小鼠异种移植模型中显示出明显改善的强大的肿瘤生长抑制作用。除了分别随剂量增加和减弱生物标志物AXIN2和β-catenin的水平外，还讨论了TCF报告基因和COLO-320DM细胞增殖研究的结果。
更新日期：2020-04-24
中文翻译：
口服有效的基于螺吲哚啉酮的坦科聚合酶抑制剂的设计与发现。
坦科聚合酶（TNKS / TNKS2）属于聚（ADP-核糖）聚合酶家族。抑制其酶活性会减弱Wnt /β-catenin信号传导，这在癌症发病机理中起着重要作用。我们以前曾报道过发现基于螺二氢吲哚的，高度选择性的，有效的坦科聚合酶抑制剂RK-287107。在这里，我们描述了导致RK-582的RK-287107的优化过程，该过程在口服时在COLO-320DM小鼠异种移植模型中显示出明显改善的强大的肿瘤生长抑制作用。除了分别随剂量增加和减弱生物标志物AXIN2和β-catenin的水平外，还讨论了TCF报告基因和COLO-320DM细胞增殖研究的结果。
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